Under Icebergs' Tip

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Most Comprehensive Analysis

One of the central tenets of HIV pathogenesis is that the virus causes a slow but progressive decline in CD4 T-cell counts. This decline is clearly evident in peripheral blood samples, but it is far more difficult to assess changes in the total CD4 T-cell population. It is estimated that only 2% of all CD4 T-cells are in the blood at any given time, making this a rather narrow window onto the body as a whole. Estimates of total body CD4 T-cell counts at different stages of HIV infection have been attempted -- sometimes based on samples from lymph nodes in addition to peripheral blood -- but there are many other inaccessible tissues where CD4 T-cells can reside. Richard Jefferys reports.

In order to try and evaluate virus-induced changes in total body CD4 T-cell counts more accurately, a group of German researchers employed an animal model of HIV infection. Thirty-two rhesus macaque monkeys infected with SIV (HIV's simian counterpart) were included in the study, and 11 uninfected monkeys served as a control group. Twelve infected macaques had to be euthanized during the study due to signs of AIDS, while the remaining 20 were sacrificed at various time points from 12-78 weeks after infection with SIV. Samples were taken from a total of 14 different body tissues, including six lymph nodes, the spleen, thymus, liver, lung, bone marrow, brain and intestine. The researchers calculated that, taken together, these tissues contain about 50% of the total number of T-cells found in a macaque. This represents the most comprehensive analysis of T-cell numbers in SIV infection conducted to date.

The most surprising result of the study was that, during the asymptomatic phase of SIV infection, the absolute numbers of both CD4 and CD8 T-cells were significantly increased compared to uninfected control animals. When T-cells in all the sampled tissues were added up, the total T-cell count was increased threefold in asymptomatic SIV-infected macaques compared to the uninfected controls. In the animals developing symptoms of AIDS, T-cell numbers in the blood were significantly decreased compared to the controls, but total body T-cell counts were similar.

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Further analysis revealed that while T-cell numbers were further increased in most non-lymphoid organs compared to asymptomatic infection, counts declined in the lymph nodes, spleen and bone marrow. The most dramatic T-cell loss in macaques with AIDS was documented in the thymus, with 8/11 animals showing a decline in thymocytes (thymic T-cells) of an order of magnitude or greater. In contrast, the number of thymocytes was slightly increased in asymptomatic infection compared to controls, although this difference did not reach statistical significance.

Focusing on CD4 T-cells, the researchers calculated the sum for all samples and found that numbers increased from an average of 3.5 billion in uninfected macaques to 6.6 billion in asymptomatic SIV infection. In animals with AIDS the average total was 4.7 billion, but the increase compared to controls was not statistically significant and the authors note that "for ethical reasons, animals were sacrificed with the first signs of immunodeficiency. For this reason and especially in the light of a complete loss of thymocytes in these animals, it seems plausible that total CD4 counts would have dropped further."

CD8 T-cells followed a similar pattern, although the increase in asymptomatic infection was even more dramatic, with counts rising from an average of 3.5 to 11.5 billion cells. Total CD8 T-cell counts in animals with AIDS were statistically indistinguishable from uninfected controls.

The research team acknowledges that these results were "completely unexpected" given the documented loss of CD4 T-cells from the blood in asymptomatic HIV infection. They believe the explanation lies in the combination of increased proliferation and redistribution of CD4 and CD8 T-cells that occurs in both SIV and HIV infections.

(To investigate the role of proliferation in this study, the expression of Ki67 (a cellular protein mainly expressed by proliferating cells) was assessed in T-cells from the various body compartments. An overall increase in turnover of 4-fold for CD4 T-cells and 12-fold for CD8 T-cells was seen in asymptomatic animals. In macaques with AIDS, CD8 T-cell proliferation remained elevated but CD4 T-cell proliferation returned to levels seen in uninfected controls.)

The implications of these data for models of HIV pathogenesis are also considered by the authors. They note that the famous "tap & drain" theory (proposed by David Ho) is not supported by their results, since it suggests that T-cell proliferation occurs in order to replenish cells that have been directly killed by HIV and thus would not explain an overall increase in total body T-cell counts or the increased proliferation of CD8 T-cells seen in this study.

Instead, the researchers believe that their data is more consistent with a model of chronic immune activation (most recently outlined by William Paul and Zvi Grossman in Nature Medicine), where the replication of HIV (and associated presence of HIV antigens in the lymph nodes) continually drives the proliferation of both CD4 and CD8 T-cells. Additionally, they point out that, "As immune activation induces trapping of T-cells in lymphoid organs and differentially influences the distribution of CD4 and CD8 T-cells, this model could also explain the altered distribution of lymphocytes found in the SIV-infected macaques."

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